Since its discovery in 1999, the ICOS-BTRP-1 costimulatory pathway has been the subject of intense investigation. ICOS, a member of the CD28 family of molecules, has been shown to be involved in Th differentiation, Tr1 differentiation, and both Th1 and Th2 effector function. The potential of ICOS to regulate effector functions in murine models of allergic airway disease has lead to the speculation that interfering with ICOS-B7RP-1 interactions may provide a novel mode of immunotherapy for allergic asthma as well as autoimmune diseases. We have recently constructed a genomic map of the ICOS locus and identified 11 polymorphisms: 10 single nucleotide polymorphisms (SNP) and 1 microsatellite site. Three of these SNPs are located 5' of the transcription start site and we have determined that one SNP is located with in a potential NFkB site. Interestingly, the most frequent allele, -1413G contains the NFkB site, while the mutant -1413A allele is no longer capable of binding NFkB. We have found that the -1413A allele that lacks the NFkB site correlates with increased expression in both luciferase promotor assays and in flow cytometry analysis of activated T cells from -1413AA and -1413GG homozygous individuals. Analysis of association of this polymorphism in the Hutterite cohert reveal an association of the -1413A allele with atopy. Another SNP in the 3' untranslated region also correlated with atopic asthma. Finally, analysis of cytokine production by the activated T cells from the -1413 AA vs. GG individuals demonstrated an increase in the IL-10 to IFN-gamma ratio. Thus, the overall hypothesis of this proposal is that the level of ICOS expression on human T cells is regulated by NFkB and that dysregulation of ICOS expression levels may directly contribute to the hyper-Th2 responses characteristic of asthma and allergies. Therefore, the goal of this grant proposal is to characterize how these allelic differences regulate ICOS expression level and how differences in surface expression of this co-stimulatory molecule affects T cell immune responses.